The treatment of pain having an inflammatory origin requires the use of different strategies, for example, the use of non steroidal ant i-inflammatory agents (NSAID's). However, depending on the pain extent, the only use of an NSAID is not capable of controlling pain satisfactorily, and additionally, important adverse effects may appear with the chronic use of these agents, especially gastric damage, gastric ulcers (Gambero et al., 2005).
The balanced or multimodal analgesia is a therapeutic approach for pain control, which is based on the combination of two or more analgesics (Dalhet, 1990). In this sense, the combination of ibuprofen, a non-steroidal anti-inflammatory agent, with different adjuvants, has been previously described.
Ibuprofen (IBU) is a non-steroidal anti-inflammatory analgesic (NSAID), relatively insoluble in water, soluble in organic solvents, with a melting point between 75 and 77° C. It has been demonstrated that ibuprofen is a potent, effective analgesic, useful in the treatment of pain from moderate to severe. Aside from its analgesic effect, it is a moderate anti-inflammatory and antipyretic agent.
Ibuprofen acts on the cyclooxygenase II enzyme, which intervenes in the process of inflammation and pain, with a plasma half life between 1.9 and 2.2 hours. Around 99% of ibuprofen is linked to albumin. It is metabolized in the liver, it has a bioavailability of from 49 to 73% when administered orally. Food reduces the absorption rate, but not the absorbed amount.
Ibuprofen belongs to the group of the 2-arylpropionic acids, it has two enantiomeric forms, R(−) and S(+), being the racemic ibuprofen one of the most used NSAIDs. The anti-inflammatory activity resides almost exclusively in the S(+) enantiomer. In vivo, ibuprofen undergoes chiral inversion, in such way that the inactive R enantiomer is converted into the active S isomer.
The commonly recommended oral dose of ibuprofen in adults is from 900 mg to 2400 mg per day, without exceeding 3,200 mg per day.
Arginine (ARG) is one of the twenty amino acids that form part of proteins, it is classified as a semi-essential amino acid. Arginine participates in the nitric oxide synthesis mechanism, which causes the relaxation of the blood vessels (vasodilatation).
This amino acid is involved in a plurality of activities of the endocrine glands, it can stimulate the immunologic function by increasing the number of leucocytes, it has a vasodilatator effect, moreover, it is involved in the synthesis of creatine, polyamines and DNA. It can decrease cholesterol levels, and stimulate the release of the growth hormone (somatotropine). It is also involved in collagen production.
Similarly to L-carnitine (L-CAR), L-arginine (L-ARG) is believed to have potentiating functions in the conversion of fatty acids into energy (muscular fuel). It can decrease cholesterol levels by improving the capacity of the circulatory apparatus, as well as stimulate the growth hormone release, reduce the body fat levels and facilitate the athletes' recovery due to its effects in withdrawing ammonia (muscular residue resulting from anaerobic exercise) from the muscles and converting it into urea, which is excreted through urine.
The combination of ibuprofen has already been described previously with different active agents. Previous clinical studies have disclosed that ibuprofen plus oxycodone or paracetamol provide analgesia and comfort to the patients, reducing the amount of ibuprofen required for managing pain, and thus, the gastropathological complications associated to its use.
Other previous studies have disclosed that ibuprofen arginate promotes a fast onset of the analgesic action, compared to ibuprofen alone (Black et al., Eur J Clin Pharmacol. 2002), basically due to the increase in the NSAID dissolution and absorption. However, there are no studies demonstrating, aside from the pharmacokinetical process (absorption), the existence of pharmacodynamical processes that favor the potentiation of the analgesic effect of ibuprofen with L-arginine. The present invention demonstrates, by means of a pre-clinic study, the pharmacodynamic progression exhibited by this composition, and additionally, it demonstrates a synergistic effect in the therapeutic activity of the combination of ibuprofen and L-arginine.
In Mexico, patent No. MX 181134, discloses a pharmaceutical composition having between 9% and 17% weight-weight (w/w) ibuprofen, combined with between 17% and 33% w/w arginine, as well as between 20%-25% w/w sodium or potassium bicarbonate, and between 25%-40% w/w sodium bitartrate, wherein up to 40% arginine is substituted by lysine. This composition is in the form of an effervescent tablet o granulate that additionally contains sweeteners and flavoring agents.
In contrast with the formulation described in patent No. MX181134, the present invention evidences synergism between two components. Additionally, the preferred interval claimed in the present invention is outside the compositions claimed by patent No. MX181134.
Patent No. MX190245 discloses a pharmaceutical composition with analgesic activity, which is adequate for manufacturing pharmaceutical preparations with complete solubility in water, characterized because it comprises from 33% to 46% w/w ibuprofen; from 34% to 51% w/w L-arginine and from 9% to 29% w/w sodium bicarbonate, wherein the molar ratio between ibuprofen and L-arginine is between 1:1.1 and 1:1.5, and the weight ratio between ibuprofen and sodium bicarbonate is between 1:0.251 and 1:0.75; said composition is in the form of an effervescent granulate that additionally contains sweeteners and flavoring agents. Moreover, the combination of the present invention is not preferred as effervescent formulations.
In contrast with the formulation described in patent No. MX190245, the present invention evidences synergism between two components.
Patent MX241292 presents a pharmaceutical composition comprising an aqueous solution of arginine and ibuprofen, wherein the molar ratio arginine to ibuprofen is lower than 1:1 and the aqueous solution is sterilized and lyophilized; ibuprofen may be (RS)-Ibuprofen or (S)-Ibuprofen and arginine may be L-arginine or D-arginine. This composition can be administered by intravenous, intramuscular and oral route.
In contrast with this formulation, the present invention refers specifically to a non-sterile combination of ibuprofen and L-arginine, in a pharmaceutical form that is preferably solid, wherein the selected ratio allows obtaining a synergistic effect in its therapeutic activity, and wherein the preferred ibuprofen/L-arginine ratio is between 1.6 and 5.6. This feature allows decreasing the use of active agents, as well as their possible adverse effects, without reducing its therapeutic activity.
To date, there are commercial pharmaceutical formulations comprising ibuprofen arginate. These formulations can be found in the form of effervescent granules with 400 mg and 600 mg or as an ibuprofen arginate formulation in injectable solution in presentations of 400 mg and 800 mg. Ibuprofen and arginine are present in equimolar ratio in the ibuprofen arginate salt, said proportion is outside the synergistic interval of the present invention. Therefore, the mentioned formulations have an additive therapeutic effect, whereas the combination of the present invention presents a synergistic effect, which allows obtaining formulations with a lower amount of the active agents and with the same analgesic-anti-inflammatory and antipyretic therapeutic effect.
We have discovered that the effective dose at 30% (ED-30) of the ibuprofen-L-arginine association, ED30 (experimental) is 52.05±0.07 mg/Kg, which is considerably lower than the theoretical ED30 of 80.6±7.6 mg/Kg. The above result suggests that after oral co-administration of ibuprofen and L-arginine, the same level of analgesic effect is achieved (30% anti-nociceptive) but it can be reduced in about 1.5 times the dose of both drugs. For this reason, the present invention discloses the active agents preferably having an ibuprofen/L-arginine ratio of 1.6 to 5.6.
With this combination it is possible to preserve the therapeutic effect by reducing the amount of ibuprofen and its possible adverse effects, such as nausea, diarrhea, abdominal pain, dizziness, gastric hyperacidity, constipation, headache and some other less frequent effects, such as edema, fever, rash and blurred vision.